The high error rate of the RNA-dependent RNA polymerases responsible for RNA viral genome replication presents an enormous challenge to successful drug therapy due to the high probability of mutations that can confer resistance to any antiviral pharmaceutical. Usually, the only solutions presented are multi-drug therapy, choosing a host-encoded target, or choosing the drug target such that resistant viruses are predicted to display only limited fitness;this latter option has not proved particularly successful due to the large amount of sequence space that can be explored by these highly mutable genomes. My laboratory has devoted considerable time to understanding the transmission genetics of positive-strand RNA viruses. Recently, we have consolidated this research to show that, for poliovirus, choices of drug target can be made so that drug-sensitive genomes dominantly inhibit the outgrowth of drug-resistant genomes. The ability of relatively unfit viruses to inhibit the growth of viruses with increased fitness derives from the intracellular amplification of positive-strand RNA viral genomes, their translation into large polyproteins and the higher-order oligomerization of several of their protein products. Here, I propose to use this understanding to identify ?dominant drug targets? for other positive-strand viruses such as rhinoviruses, coxsackieviruses, hepatitis C virus, Dengue virus and West Nile virus, informed by analogy with poliovirus and tested by direct genetic and biochemical investigation. This new paradigm will facilitate the development of therapeutics for which there is reduced danger of outgrowth of the inevitable drug-resistant genomes. My thesis is that theoretical and experimental understanding of the unusual genetics of intracellular viral growth can lead to the identification of ?Achilles? heels? for each targeted positivestand RNA virus, and possibly for other intracellular pathogens as well.